Program Director/Principal Investigator {Last, First, Middle): P a i g e n , B e v e r l y J PROJECT SUMMARY (See instnjctions}: Heart disease is the major cause of death in industrialized societies. Lifestyle changes and the many drugs available to reduce LDL cholesterol have done a great deal to reduce heart disease, and the major avenue to further therapeutic progress lies in learning how to raise HDL, a major protection against heart disease. The mouse is an excellent model for finding HDL genes because the quantitative trait loci (QTL) for HDL in mouse and human are found in concordant locations. In the extension period we will test the candidacy of Grin3a, Etv6, the 5 genes on Chr 19, and the candidate genes from the B6xC57L cross. The first step is to obtain and test knockout models for each of them. After the generation, these models will first be tested for differences in HDL cholesterol levels. When a difference is observed, we will obtain gene expression profiles from liver, adipose tissue, and macrophages. These profiles will direct us toward the pathway through which the candidate gene impacts HDL metabolism. Once these pathways are identified we will hypothesize the role of the gene within the pathway and design appropriate experiments to test the hypothesis. RELEVANCE (See instructions): The major goal is to identify the genes and pathways that affect HDL cholesterol, which provides protection against the leading cause of death, heart disease. Identifying these HDL genes will uncover novel drug targets, and understanding the pathways of HDL regulation will elucidate the drug targets likely to have the greatest impact on HDL. Raising HDL is predicted to decrease heart disease incidence.